“Hurts less, lasts longer”; a qualitative study on experiences of young people receiving high-dose subcutaneous injections of benzathine penicillin G to prevent rheumatic heart disease in New Zealand

Background Four-weekly intramuscular (IM) benzathine penicillin G (BPG) injections to prevent acute rheumatic fever (ARF) progression have remained unchanged since 1955. A Phase-I trial in healthy volunteers demonstrated the safety and tolerability of high-dose subcutaneous infusions of BPG which resulted in a much longer effective penicillin exposure, and fewer injections. Here we describe the experiences of young people living with ARF participating in a Phase-II trial of SubCutaneous Injections of BPG (SCIP). Methodology Participants (n = 20) attended a clinic in Wellington, New Zealand (NZ). After a physical examination, participants received 2% lignocaine followed by 13.8mL to 20.7mL of BPG (Bicillin-LA®; determined by weight), into the abdominal subcutaneous tissue. A Kaupapa Māori consistent methodology was used to explore experiences of SCIP, through semi-structured interviews and observations taken during/after the injection, and on days 28 and 70. All interviews were recorded, transcribed verbatim, and thematically analysed. Principal findings Low levels of pain were reported on needle insertion, during and following the injection. Some participants experienced discomfort and bruising on days one and two post dose; however, the pain was reported to be less severe than their usual IM BPG. Participants were ‘relieved’ to only need injections quarterly and the majority (95%) reported a preference for SCIP over IM BPG. Conclusions Participants preferred SCIP over their usual regimen, reporting less pain and a preference for the longer time gap between treatments. Recommending SCIP as standard of care for most patients needing long-term prophylaxis has the potential to transform secondary prophylaxis of ARF/RHD in NZ and globally.

Pain and frequency of the usual SP regimen are presented as the only limiting factors impacting adherence to the injection regimen.As I am sure the authors are aware, these are just some of the limiting factors.See synopsis for a more accurate description to do with adherence.
One of the strongest outcomes of this trial is the potential to provide another SP option for patients to choose from.Query as to what happened at the end of the trial to the 19 participants who strongly preferred SCIP needs to be included.

Title:
The title should clearly show the genre of the research and the study site.

Suggestions:
"Hurts less, lasts longer": a qualitative study on experiences of young people receiving highdose subcutaneous infusions of benzathine penicillin G to prevent rheumatic heart disease in Aotearoa (or New Zealand).
Or A qualitative study on experiences of young people receiving high-dose subcutaneous infusions of benzathine penicillin G in a Phase-II trial to prevent rheumatic heart disease in Aotearoa (or New Zealand): "hurts less, lasts longer".

Abstract:
Line 7 Methodology: Need to include "methodology".Currently just states methods (interviews and observations-and the trial process).Suggest adding at the start of this paragraph: "This study used Kaupapa principles to explore Māori and Pacific young peoples' experiences."Line 17 Remove the emotive word "overwhelmingly" to fit with academic writing style.Line 19 Suggest replacing "treatments" with injections.
No matter which method patients choose, it is still an injection.

Synopsis:
In general, A solely biomedical description of ARF and RHD in a qualitative paper.This likely reflects the fields of expertise of most of the authors.Suggestions below Line 25 Suggest inserting the following text at the end of the sentence after the word infection: "…predominantly among people living in socioeconomic disadvantage." Line 29 Needs a more accurate description to do with adherence problems.Change sentence to: "The effectiveness of this approach is limited by complex issues including the young age of patients and health system frailties (as in your ref 8).However, pain, fear, and the frequency of injection are recognised as common barriers to the injection adherence."Line 34 Replace "overwhelmingly" with strongly Line 35-36 Put the number 70 first to match with the preceding text Introduction: Line 48 "…for Indigenous Māori".
Debates exist around use of this term in Aotearoa.Could distract some readers.Note that in ref 4, some of the same authors as in this paper use the phrase "people of Māori and Pacific Islander ethnicity".Line 58 Typo-recommend should be recommended Line 62 Change beginning of sentence to: "Pain and fear associated with IM……." Line 67 New formulations are urgent but adherence to the regimen is more complex than just injection pain and there is an equally urgent need, for instance, to improve housing in NZ for Māori and Pacific people to prevent ARF.Suggestions for new sentence: However, to improve adherence and prevent disease progression, new formulations of long-acting penicillins are warranted.or Improving the formulation of long-acting penicillin has potential to improve adherence and prevent disease progression.Line 73 and 74 For later ref in last paragraph of the Discussion, need to mention the global experts' conclusions about cold chain and cost mentioned here.Line 79 End of sentence change to "no significant adverse effects" Line 89 and 90 Note: These lines show the additional measures that should be available to address pain and fear of injection episodes for young people thus providing evidence that the authors do know that the injection experiences are more complex than pain alone.Line 97 Suggest change to: This paper reports on the qualitative component of the SCIP-II trial aiming to explore participants' experiences of SCIP compared with the usual intramuscular regimen.

Methods
Further information that aligns with the Kaupapa principles is needed in describing recruitment of participants.
Line 93 Suggested rewrite: "In brief, participants with ARF, were identified through a regional register of secondary prophylaxis.X were invited to be part of the study by attending an outpatient clinic (designated for the study?) in Wellington, NZ."A brief statement of how the participants were invited is needed.
Were they contacted by phone, email or in person?And by whom?How were explanations of the study provided?This info is needed to demonstrate a Kaupapa approach of respecting participants' equal power to choose to take part in the study or not.Finally, "Twenty participants agreed to participate in the study which ran from 21 st November 2022 until 20 th March 2023.Participants were followed for 70 days after their initial clinic visit where they received SCIP."I note in the ethics section that consent forms were available in Te Reo Māori and Samoan.This implies that language was an issue?? What languages were the interviews conducted in?Were interpreters needed or used?Line 122 Observational data were collected by the study nurse or researcher.Insert their initials.Hopefully we know that they are Māori or Pacifica or not by this point in the paper to reflect Kaupapa principles and transparency.Line 127 Ambiguous and needs more detail about: 'a community nurse' what is her role and involvement with SP or other?'two researchers': which ones? Were they clinicians, qualitative researchers, authors on this paper?Convince the readers that these interviews were relevant and added value.Line 129 Remove 'quantitative', the pain was measured quantitatively.
Quantitative is implied in the scoring system used.
Qualitative studies can also include quantitative methods.Line 132 Insert "a reduction of" 1.3 and 1.8 respectively….

Data analysis
Line 137 Change to: Interviews and field observations were transcribed verbatim for analysis.
Line 138 Transcripts were read repeatedly by [insert initials] and remove "one investigator" Line 139 Thematic saturation is a given in qual research.This sentence and the following sentence could be removed.Better to state that there was early congruence in themes arising from transcripts.Line 142 Here we finally hear that the study nurse, a community nurse, and two researchers were present during infusions.This info needs to come in line 127.This sentence not needed here as it is previously explained that they were interviewees.

Line 144 and 145
This is an important sentence that needs further information to verify the Kaupapa framework.The codes and themes were presented Māori and Pacific researchers (the first time we hear such researchers were involved).We need to hear their responses.Did they adjust any codes, make suggestions, provide insight into cultural aspects?Additionally, was any feedback given to participants?Did this lead to any changes in themes?

Ethical approval
Line 153 Were the consent forms also available in English?

Lines 159 and 160
Age range states 6 -32 but table has youngest as 7 years.Suggest remove "Indigenous" Thematic analysis Line 165 Suggest: "Overall, the thematic analysis……… Some initial anxiety from participants to with… what?Fear of unknown?Dealing with unfamiliar practitioners?Line 171 Change to "Anxiety prior to SCIP" or "Anxiety in anticipation of SCIP" Line 172 How was anxiety evident?"Anxiety was either stated or observed in many participants."Line 189 …short, sharp or caused a stinging sensation that quickly subsided.Line 196 …participants described having no pain or minimal pain during…… Line 212 Tautology: don't need small with minority Line 216 "Two participants experienced some distress and discomfort, with corresponding pain scores of seven."Without a prior understanding of …… Line 223 Move this sentence to Discussion.Line 231 "…had resumed usual activities."Line 255 Change heading to: Strong preference to remain on three-monthly SCIP rather than BPG Line 257 Line 258 No need for brackets Suggest change to: "The study nurse observed participants' sense of relief at the prospect of being able to change from IM BPG to SCIP".This is why readers need to know if it was explained to participants at the start of the study if ongoing SCIP would be an option at the end of the study.It was predictable that if a strong preference emerged for SCIP that this question about continuing SCIP would arise among participants.This meant that participants had less interruption to their usual work or school schedules to obtain injections and increased their freedom to travel.Line 289 Suggest change to: "Administering SCIP through a series of slow pushes enabled more control in the rate of delivery in comparison to the ……" Line 301 Change to…we did not ask about "participants usual or general pain tolerance prior to the study".Line 302 Remove the words "and contrast" Line 304 to 309 These sentences are a red flag to qualitative researchers.As it currently reads, there are negative assumptions that I doubt the authors intend about some participants and which defy Kaupapa principles.Please review these sentences with Māori researchers for insight and clarity.For instance, were the difficulties due to language or cultural barriers or unknown interviewer?Line 313 Suggest addition: "….participants were able to discuss life issues as well as challenges with regular IM BPG indicating their preference for holistic approaches in healthcare delivery" Line 314 to 316 I think you mean that use of the Kaupapa approach as an Indigenous methodology helped participants to feel empowered and treated as partners rather than subjects of research.This sentence needs changing.Line 318 to 324 This study reports a great breakthrough in SP.However, we need to be mindful that the current formulation of SCIP is only possible where there is a cold chain and where it can be afforded.This indicates that more work needs to be done for those sites that don't have these advantages.Suggest a reword: "SCIP utilising prefilled syringes is preferred over IM BPG as a tolerable and acceptable route of administration for children and young adults with ARF in Wellington, NZ.Extending this study to support widespread choice of SCIP throughout NZ for patients requiring secondary prophylaxis over a prolonged period will enable better assessment of key measures over time.We note that SCIP does not yet align with all recommendations of global experts in that it should be cold chain independent and of comparable cost for greatest global benefit.It would be useful to undertake an economic evaluation of SCIP in comparison to IM BPG.Further work on cold chain independence is warranted.Current evidence suggests that SCIP will likely become the standard of care for most patients needing long-term prophylaxis.SCIP has the potential to improve patient experiences which may assist prevention of disease progression and death, transforming prophylaxis of ARF/RHD both in NZ and globally.

Table line 106
For clarity, change "Number of vials" to "Number of prefilled syringes" Line 110 Change data collection here to a new section heading, "Methodology".This new Methodology section would assist flow if it were placed before the Methods section because it provides rationale for why certain methods were undertaken.Stating the methodology strengthens qualitative papers and is one indicator of quality of a study.Not being clear about methodology is a common trap in qualitative components of drug trials.Suggested text below Methodology Line 111 Suggested example to replace existing text on Kaupapa principles in research.Current explanations of Kaupapa in the paper are vague and unconvincing for the reader: "This qualitative study used Kaupapa Māori research principles as a framework.These principles prioritise Māori perspectives and wellbeing by attending to unequal power relations and rejecting deficit explanations."This is where you need to state that the study involved Māori or Pacific researchers, nurses of assistants.How were participants given feedback on results?Did they know upfront that it was a trial and that SCIP would not be available after the study ended?How did you mitigate a sense of being experimented on?Line 116 This subheading of "data collection" describes methods.Suggest moving it to Methods section, below the table 1. Commence with Participant observations….Note, interviews and observations are methods, not methodology.Text to do with Kaupapa now under Methodology.Line 120 All interviews occurred face to face by whom?Initials of researcher suffice.